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      Effects of splanchnic vasoconstrictors on liver regeneration and survival after 90% rat hepatectomy

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          Posthepatectomy liver failure is a serious complication and considered to be caused by increased portal pressure and flow. Splanchnic vasoactive agents and propranolol are known to decrease portal pressure. The aim of this study was to identify optimal candidates with potential for clinical use among somatostatin, terlipressin, and propranolol using rats with 90% hepatectomy.


          Rats were divided into 5 groups: sham operation (n = 6), control (n = 20), propranolol (n = 20), somatostatin (n = 20), and terlipressin group (n = 20). Seven-day survival rates and portal pressure change were measured, and biochemical, histologic, and molecular analyses were performed.


          Portal pressure was significantly decreased in all 3 treatment groups compared to control. All treatment groups showed a tendency of decreased liver injury markers, and somatostatin showed the most prominent effect at 24 hours postoperatively. Histologic liver injury at 24 hours was significantly decreased in propranolol and terlipressin groups (P = 0.016, respectively) and somatostatin group showed borderline significance (P = 0.056). Hepatocyte proliferation was significantly increased after 24 hours in all treatment groups. Median survival was significantly increased in terlipressin group compared to control group (P < 0.01).


          Terlipressin is considered as the best candidate, while somatostatin has good potential for clinical use, considering their effects on portal pressure and subsequent decrease in liver injury and increase in liver regeneration.

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          Most cited references 28

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          Liver regeneration.

          Liver regeneration after the loss of hepatic tissue is a fundamental parameter of liver response to injury. Recognized as a phenomenon from mythological times, it is now defined as an orchestrated response induced by specific external stimuli and involving sequential changes in gene expression, growth factor production, and morphologic structure. Many growth factors and cytokines, most notably hepatocyte growth factor, epidermal growth factor, transforming growth factor-alpha, interleukin-6, tumor necrosis factor-alpha, insulin, and norepinephrine, appear to play important roles in this process. This review attempts to integrate the findings of the last three decades and looks toward clues as to the nature of the causes that trigger this fascinating organ and cellular response.
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            A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome.

             F Regenstein,  Peter Teuber,   (2008)
            Hepatorenal syndrome (HRS) type 1 is a progressive functional renal failure in subjects with advanced liver disease. The aim of this study was to evaluate the efficacy and safety of terlipressin, a systemic arterial vasoconstrictor, for cirrhosis type 1 HRS. A prospective, randomized, double-blind, placebo-controlled clinical trial of terlipressin was performed. Subjects with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) or placebo plus albumin in both groups. The dose was doubled on day 4 if the serum creatinine (SCr) level did not decrease by 30% of baseline. Treatment was continued to day 14 unless treatment success, death, dialysis, or transplantation occurred. Treatment success was defined by a decrease in SCr level to
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              Role of platelets on liver regeneration after 90% hepatectomy in mice.

              Mortality after 90% partial hepatectomy in mice was associated with severe acute liver failure. Recently, we revealed that platelets have a strong promotional effect on hepatic regeneration. In the present study, we investigated the effect of thrombocytosis on liver regeneration after 90% hepatectomy in mice. For thrombocytosis induction PEG-rHuMGDF was injected 5 days before operation. Hepatectomy, sparing only the caudate lobe, was performed in normal and thrombocytotic BALB/c mice. Survival rate, platelet number, liver weight/body weight ratio, proliferating cell nuclear antigen, serum parameters, signal transduction and overexpressed genes were examined. Platelet number was significantly higher in thrombocytotic group. All mice in normal group died within 30 h after hepatectomy. Survival rate in thrombocytotic group was 6/11 at 30 h and 3/11 one week after hepatectomy. Activation of Akt and STAT3 signaling pathways in thrombocytotic group was observed earlier and recognized to be stronger compared to normal group. Cell cycle, signaling pathways, metabolism and transport genes were significantly overexpressed in thrombocytotic group up to 24h after hepatectomy. Under the thrombocytotic condition, liver regeneration occurred even in 90% hepatectomized mice. Platelets contribute to cell cycle progression and metabolic pathways in addition to preventing acute liver failure.

                Author and article information

                Ann Surg Treat Res
                Ann Surg Treat Res
                Annals of Surgical Treatment and Research
                The Korean Surgical Society
                March 2018
                28 February 2018
                : 94
                : 3
                : 118-128
                [1 ]Department of Surgery, Korea University College of Medicine, Seoul, Korea.
                [2 ]Department of Biomedical Science, Korea University College of Medicine Graduate School, Seoul, Korea.
                [3 ]Department of Pathology, Korea University College of Medicine, Seoul, Korea.
                Author notes
                Corresponding Author: Dong-Sik Kim. Division of HBP Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea. Tel: +82-2-920-6620, Fax: +82-2-921-6620, kimds1@ 123456korea.ac.kr

                *Dong-Sik Kim and Woong Bae Ji contributed equally to this study as co-first authors.

                Copyright © 2018, the Korean Surgical Society

                Annals of Surgical Treatment and Research is an Open Access Journal. All articles are distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: National Research Foundation of Korea, CrossRef http://dx.doi.org/10.13039/501100003725;
                Award ID: 2014R1A1A1A05006371
                Award ID: 2017R1A2B2005754
                Original Article


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